This fellowship will support the interdisciplinary research and training of Mr. Christopher Gromisch under the co-sponsorship of Boston University (BU) professors Dr. Mark Grinstaff (drug delivery, biomaterials, and chemistry) and Dr. Victoria Herrera (cancer, DEspR cell biology, and in vivo models), along with mentorship and advising from Dr. Nelson Ruiz-Opazo (molecular biology, in vitro models, and genetics), and Dr. Hamant Roy (pancreatic cancer/GI specialist). The research arm of this proposal advances a humanized monoclonal antibody as a first-in class therapy against pancreatic ductal adenocarcinoma (PDAC). The antibody selectively targets the unique dual endothelin1/signal peptideVEGF receptor (DEspR) that is highly expressed on cancer stem-like cells (CSCs) and non-CSC tumor cells within the tumor niche ? DEspR-humab. Aim 1 characterizes the role of DEspR in tumor cell survival by investigating the mechanism of cell death (necroptosis vs. apoptosis and Apaf1 and BIRC3) from receptor binding by DEspR-humab, the role of cellular stress in directing cell death, and the role of nuclear shuttling of the receptor in cancer cells. These studies will provide a fundamental understanding of DEspR-humab mechanism of action. Aim 2 develops a novel controlled site-specific method for conjugation of two drugs to DEspR-humab and evaluates the in vitro efficacy of the DEspR-humab and an antibody drug conjugate (ADC) of DEspR-humab and mertansine, a potent microtubule-targeted cytotoxic agent, in a PDAC cells and PDAC derived CSCs. Preliminary in vivo data show that DEspR-humab treatment alone outperforms gemcitabine, thus providing support and motivation for the proposed studies. Drs. Grinstaff and Herrera will continue to meet regularly with the fellow as part of his personalized three-year NIH training plan, which includes: 1) training in molecular oncology, cancer biology, chemical synthesis, pharmacology, drug delivery, and in vitro and in vivo models; 2) studying a novel antibody for the treatment of PDAC; 3) mentoring by basic scientists and physicians; 4) training in responsible conduct of research; 5) spending time in the endoscopy suites with Dr. Roy and continuing clinical rotations; 6) attending BUSM Oncology and GI Grand Rounds to remain up-to-date with best clinical practices; 7) attending seminars in the Pharmacology, Chemistry, and Medicine Departments; 8) preparing for and presenting at local and national conferences (e.g., American Gastroenterology Association, American Society of Clinical Oncology, National M.D./Ph.D. Student Conferences, and Gordon) to share research findings and build professional networks; and 9) guiding his professional training in the framework of his individual development plan. This combined research and training program provides the fellow a unique opportunity to learn, to contribute to cancer therapeutics, and to advance his development as a physician scientist. This fellowship establishes resources for clinical mentoring and an interdisciplinary research project with significant basic and clinical outcomes.